1. Field of the Invention
The present invention relates to biologically active polyquaternary polymers, and more particularly, to the use of ionene polymers to selectively bind negatively charged cells.
2. Description of the Prior Art
Early work with cell electrophoresis suggested that neoplastic, proliferating, and embryonal cells have a higher electro-negative surface charge than other types of cells. Each type of cell exhibits its own characteristic electronegativity, i.e. lymph node and spleen cells are more negative than thymocytes and macrophages. Cell membrane acid anions are the major cause of excess surface negative charge. More recently, a uniformity of electrokinetic pattern between normal and leukemic cells has been reported. The malignant cell lines HeLa (cervical cancer), HEp2 (laryngeal carcinoma), 256 (rat sarcoma), normal lymphocytes, and normal and malignant trophoblastic cells were found to have a common cell surface coating of an ionic nature not generally found for other normal cell types tested. Electron microscopic studies have also shown that malignant cells have an increased surface thickness of mucopolysaccaride material, containing terminal groups of negatively charged sialic acid moieties.
The use of polycations to cure or treat malignant cells is indicated by the electrostatic characteristic of the cell membrane. Polycation molecules may be monomeric or polymeric, of low or high molecular weight, may be linear or branched, and may have their charged quaternary group, (ammonium, sulfonium, or phosphonium), integral or pendant to the chain, with resulting biological properties extremely dependent upon these parameters. Many water soluble compounds are commercially available.
A difficulty in attempting to exploit electrostatic phenomenon in therapy of malignant disease stems from the lack of specificity for tumor cells by polycations and also the constantly changing surface chemistry of cell membranes. Nevertheless, the possibility of employing polycations for preferential growth inhibition of malignant cells has been attempted.
Several classes of polycations, primarily quaternary polyethylene imine (PEI), polypropylene imine (PPI), polyvinylimidazolinium (PVA), and diethyl amino ethyl dextran (DEAD) have been found to inhibit the growth of allogeneic and syngeneic tumors in mice at non-toxic levels to the host. Anti-tumor activity appears related to the polycation type, molecular weight, zeta potential and route of injection. While these agents are cytotoxic, only a few have been shown to exhibit any specificity for tumor cells, i.e. the capability of non-toxic action on normal cells while exhibiting toxic activity with respect to malignant cells. Furthermore, these commercial polymers are not well characterized as to structure and molecular weight and are of questionable purity.
Monomeric polyquaternary cations of aliphatic and heterocyclic structure such as ditertiary aliphatic diamines and bisquaternary pyridine compounds have been suggested for use as curariform and anti-tumor agents. The binding efficiency, toxicity and duration of activity have not been totally satisfactory.